Ready-to-use ketamine premix formulation

Abstract

The invention relates to a sterile, ready-to-use, stable aqueous solution of ketamine suitable for direct intravenous infusion to a patient in need thereof, wherein the composition is disposed within a sealed infusion container as a premixture. The invention further relates to aqueous solutions of ketamine that are free of antimicrobials such as benzethonium chloride and are shelf-stable. The pharmaceutical compositions can be used, for example, wherein the subject is in need of anesthesia for a diagnostic or a surgical procedure.

We claim: 
     
         1 . A ketamine product comprising an aqueous ketamine solution comprising about 0.5 to about 2.5 mg/mL ketamine, a tonicity adjusting agent, and water for injection, wherein the ketamine solution is preservative-free and anti-microbial free, wherein the ketamine product is sterile and ready-to-use (RTU), wherein the pH of the aqueous ketamine solution is about 3 to about 6, and wherein the ketamine content of the aqueous ketamine solution after long-term storage for 12 months at 25° C.±2° C./40% RH±5% RH is 97% or greater compared to the ketamine content before storage. 
     
     
         2 . The ketamine product of  claim 1 , wherein the ketamine product has been terminally sterilized. 
     
     
         3 . The ketamine product of  claim 2 , wherein the ketamine product has been autoclaved. 
     
     
         4 . The ketamine product of  claim 1 , wherein the ketamine is at a concentration of about 1 mg/mL to about 2 mg/mL. 
     
     
         5 . The ketamine product of  claim 1 , wherein the aqueous ketamine solution has an osmolality of about 270-330 mOsmol/kg. 
     
     
         6 . The ketamine product of  claim 1 , wherein the aqueous ketamine solution is contained in an infusion bag comprising at least one port sealed with a closure. 
     
     
         7 . The ketamine product of  claim 6 , wherein the infusion bag comprises a flexible single-layer film or a flexible multilayer film. 
     
     
         8 . The ketamine product of  claim 6 , wherein the flexible single layer film or the flexible multilayer film comprises a polymer selected from the group consisting of polyethylene, polypropylene, modified polyolefin-polyethylene polymers, styrene-polyolefin based polymers, block copolymers, and a combination thereof, wherein at least one layer comprises polypropylene styrene-block copolymer. 
     
     
         9 . The ketamine product of  claim 6 , wherein the infusion bag is contained within an overwrap. 
     
     
         10 . The ketamine product of  claim 9 , wherein the overwrap is not vacuum-sealed, and wherein the ketamine product comprises air between the infusion bag and the overwrap. 
     
     
         11 . The ketamine product of  claim 1 , wherein the tonicity adjustment agent comprises sodium chloride, dextrose, glycerin, mannitol, potassium chloride, or any combination thereof. 
     
     
         12 . The ketamine product of  claim 1 , wherein the ketamine or a pharmaceutically acceptable salt thereof is chemically stable following 24 months storage at 25° C.±2° C. with relative humidity (RH) at 40% ±5%. 
     
     
         13 . The ketamine product of  claim 1 , wherein the ketamine content of the aqueous ketamine solution after accelerated storage at 40° C.±2° C./<25% RH for 6 months is greater than 97%. 
     
     
         14 . A method of preparing the ketamine product of  claim 1  comprising:
 i) preparing an aqueous ketamine solution comprising about 0.5 to about 2.5 mg/mL ketamine, a tonicity adjusting agent, and water for injection; 
 ii) filtering the solution of step (i); 
 iii) filling the solution of step (ii) into an infusion bag; 
 iv) terminally sterilizing the infusion bag of step (iii) 
 wherein the method further comprises overwrapping the infusion bag, wherein the overwrapping step comprises overwrapping the infusion bag of step (iii) prior to terminally sterilizing the infusion bag or overwrapping the terminally sterilized infusion bag of step (iv) after terminal sterilization. 
 
     
     
         15 . A method of treating a subject in need of analgesia, comprising administering the ketamine product of  claim 1  to the subject as a continuous infusion. 
     
     
         16 . A ketamine product comprising an aqueous ketamine solution comprising about 0.5 to about 2.5 mg/mL ketamine, sodium chloride, and water for injection, wherein the ketamine solution is preservative-free and anti-microbial free, wherein the ketamine product has been aseptically filled or wherein the ketamine solution is contained in a terminally sterilized, ready-to-use infusion container, wherein the ketamine content of the aqueous ketamine solution after long-term storage for 6 months at 25° C.±2° C./40% RH±5% RH is 97% or greater compared to the ketamine content before storage. 
     
     
         17 . The ketamine product of  claim 16 , wherein the ketamine content of the aqueous ketamine solution after accelerated storage at 40° C.±2° C./<25% RH for 6 months is greater than 97% and/or wherein the ketamine content of the aqueous ketamine solution after long-term storage for 12 months at 25° C.±2° C./40% RH±5% RH is 97% or greater compared to the ketamine content before storage. 
     
     
         18 . The ketamine product of  claim 16 , wherein the ketamine or a pharmaceutically acceptable salt thereof is chemically stable following 24 months of storage at 25° C.±2° C. with relative humidity (RH) at 40% ±5%. 
     
     
         19 . The ketamine product of  claim 16 , wherein the ketamine product has a shelf-life of more than twelve months when stored at a controlled room temperature between 15-30° C. 
     
     
         20 . A method of treating a subject in need of analgesia, comprising administering an aqueous ketamine solution comprising about 0.5 to about 2.5 mg/mL ketamine, a tonicity adjusting agent, and water for injection to the subject as a continuous infusion, wherein the aqueous ketamine solution is contained in an infusion bag, and wherein the aqueous ketamine solution is chemically stable following 12 months storage at 25° C.±2° C. with relative humidity (RH) at 40% ±5%.